Chemical Compounds

ABSTRACT

The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof  
                 
wherein R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: 
             halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ;        R 1  is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7  or cyano;    R 2  is hydrogen, C3-C7 cycloalkyl, or a group R 9 ;    R 3  is C3-C7 cycloalkyl, or a group R 9 ; or    R 2  and R 3  together with N form a 5-14 membered heterocycle, which may be substituted by 1 to 3 R 10  groups;    R 4  is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;    R 5  is a C1-C4 alkyl, —OR 6  or —NR 6 R 7 ;    R 6  is hydrogen or C1-C6 alkyl;    R 7  is hydrogen or C1-C6 alkyl;    R 8  is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11  groups;    R 9  is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl;    R 10  is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11  groups;    R 11  is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; X is carbon or nitrogen; n is 1 or 2; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

This application is a continuation of application Ser. No. 10/483,792,filed Jan. 14, 2004, now pending, which is a 371 of InternationalApplication No. PCT/EP02/07865, filed Jul. 15, 2002.

The present invention relates to bicyclic derivatives, to processes fortheir preparation, to pharmaceutical compositions containing them and totheir use in therapy.

The first corticotropin-releasing factor (CRF) was isolated from ovinehypothalami and identified as a 41-amino acid peptide (Vale et al.,Science 213: 1394-1397,1981). CRF has been found to produce profoundalterations in endocrine, nervous and immune system function. CRF isbelieved to be the major physiological regulator of the basal andstress-release of adrenocorticotropic hormone (“ACTH”), Bendorphin andother proopiomelanocortin (“POMC”)-derived peptides from the anteriorpituitary (Vale et al., Science 213: 1394-1397,1981).

In addition to its role in stimulating the production of ACTH and POMC,CRF appears to be one of the pivotal central nervous systemneurotransmitters and plays a crucial role in integrating the body'soverall response to stress.

Administration of CRF directly to the brain elicits behavioral,physiological and endocrine responses identical to those observed for ananimal exposed to a stressful environment. Accordingly, clinical datasuggests that CRF receptor antagonists may represent novelantidepressant and/or anxiolytic drugs that may be useful in thetreatment of the neuropsychiatric disorders manifesting hypersecretionof CRF.

The first CRF receptor antagonists were peptides (see, e.g., Rivier etal., U.S. Pat. No. 4,605,642; Rivier et al., Science 224: 889,1984).While these peptides established that CRF receptor antagonists canattenuate the pharmacological responses to CRF, peptide CRF receptorantagonists suffer from the usual drawbacks of peptide therapeuticsincluding lack of stability and limited oral activity. More recently,small molecule CRF receptor antagonists have been reported.

WO 95/10506 describes inter alia compounds of general formula (A) withgeneral CRF antagonist activity

wherein Y may be CR29; V may be nitrogen, Z may be carbon, R3 maycorrespond to an amine derivative and R4 may be taken together with R29to form a 5-membered ring and is —CH(R28) when R29 is-CH(R30). There areno specific disclosures of compounds corresponding to this definition.

WO 95/33750 also describes compounds of general formula (B) having CRFantagonistic activity,

in which A and Y may be nitrogen and carbon and B may correspond to anamine derivative. There are no specific disclosures of compoundscorresponding to this definition.

WO 98/08846 describes compounds of general formula (C) having CRFantagonistic activity,

wherein A may be carbon, G may be nitrogen or carbon, B may be an aminoderivative and the other groups have the meanings as defined.

Due to the physiological significance of CRF, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF receptorremains a desirable goal. Such CRF receptor antagonists would be usefulin the treatment of endocrine, psychiatric and neurologic conditions orillnesses, including stress-related disorders in general.

While significant strides have been made toward achieving CRF regulationthrough administration of CRF receptor antagonists, there remains a needin the art for effective small molecule CRF receptor antagonists. Thereis also a need for pharmaceutical compositions containing such CRFreceptor antagonists, as well as methods relating to the use thereof totreat, for example, stress-related disorders. The present inventionfulfills these needs, and provides other related advantages.

In particular the invention relates to novel compounds which are potentand specific antagonists of corticotropin-releasing factor (CRF)receptors.

The present invention provides compounds of formula (I) includingstereoisomers, prodrugs and pharmaceutically acceptable salts orsolvates thereof

-   -   wherein    -   R is aryl or heteroaryl, each of which may be substituted by 1        to 4 groups selected from:        -   halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6            alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R₅, nitro,            —NR₆R₇, cyano, and a group R₈;    -   R₁ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo        C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR₆R₇ or cyano;    -   R₂ is hydrogen, C3-C7 cycloalkyl, or a group R₉;    -   R₃ is C3-C7 cycloalkyl, or a group R₉; or    -   R₂ and R₃ together with N form a 5-14 membered heterocycle,        which may be substituted by 1 to 3 R₁₀ groups;    -   R₄ is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;    -   R₅ is a C1-C4 alkyl, —OR₆ or —NR₆R₇;    -   R₆ is hydrogen or C1-C6 alkyl;    -   R₇ is hydrogen or C1-C6 alkyl;    -   R₈ is a 5-6 membered heterocycle, which may be saturated or may        contain one to three double bonds, and which may be substituted        by 1 or more R₁₁ groups;    -   R₉ is a C1-C6 alkyl that may be substituted by one or more        groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6        alkoxy, hydroxy, haloC1-C6 alkyl;    -   R₁₀ is a group R₈, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy,        halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6        alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR₆R₇, phenyl which        may be substituted by 1 to 4 R₁₁ groups;    -   R₁₁ is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6        alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy,        halogen, nitro, cyano, or C(O)NR₆R₇;    -   X is carbon or nitrogen;    -   n is 1 or 2.

Acid addition salts of the free base amino compounds of the presentinvention may be prepared by methods well known in the art, and may beformed from organic and inorganic acids. Suitable organic acids includemaleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic,p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic,citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic,palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitableinorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric,and nitric acids. Thus, the term “pharmaceutically acceptable salt” ofstructure (I) is intended to encompass any and all acceptable saltforms.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol, sulfhydryl andamine functional groups of the compounds of structure (I). Further, inthe case of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as recemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The term C1-C6 alkyl as used herein as a group or a part of the grouprefers to a linear or branched alkyl group containing from 1 to 6 carbonatoms; examples of such groups include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert butyl, pentyl or hexyl.

The term C3-C7 cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; whileunsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and thelike.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term halo C1-C6 alkyl, or halo C1-C2 alkyl means an alkyl grouphaving one or more carbon atoms and wherein at least one hydrogen atomis replaced with halogen such as for example a trifluoromethyl group andthe like.

The term C2-C6 alkenyl defines straight or branched chain hydrocarbonradicals containing one or more double bond and having from 2 to 6carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl andthe like.

The term C1-C6 alkoxy group may be a linear or a branched chain alkoxygroup, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy and the like.

The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as definedbefore substituted with at least one halogen, preferably fluorine, suchas OCHF₂, or OCF₃.

The term C2-C6 alkynyl defines straight or branched chain hydrocarbonradicals containing one or more triple bond and having from 2 to 6carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl,3-methyl-1-butynyl and the like.

The term aryl means an aromatic carbocyclic moiety such as phenyl,biphenyl or naphthyl.

The term heteroaryl means an aromatic heterocycle ring of 5 to 10members and having at least one heteroatom selected from nitrogen,oxygen and sulfur, and containing at least 1 carbon atom, including bothmono-and bicyclic ring systems.

Representative heteroaryls include (but are not limited to) furyl,benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl,isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl,and quinazolinyl.

The term 5-14 membered heterocycle means a 5 to 7-membered monocyclic,or 7-to 14-membered polycyclic, heterocycle ring which is eithersaturated, unsaturated or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized, includingbicyclic rings in which any of the above heterocycles are fused to abenzene ring as well as tricyclic (and higher) heterocyclic rings. Theheterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined above. Thus, in addition tothe aromatic heteroaryls listed above, heterocycles also include (butare not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

The term 5-6 membered heterocycle means, according to the abovedefinition, a 5-6 monocyclic heterocyclic ring which is eithersaturated, unsaturated or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized. Heterocyclesinclude heteroaryls as defined above. The heterocycle may be attachedvia any heteroatom or carbon atom. Thus, the term include (but are notlimited to) morpholinyl, pyridinyl, pyrazinyl, pyrazolyl, thiazolyl,triazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

Representative compounds of this invention include the followingstructure (Ia) and (Ib)

In one preferred embodiment in which n is 1, according to the definitionof the compounds of formula (I) above, the CRF receptor antagonists ofthis invention have structure (Ia), and, when n is 2, then the CRFreceptor antagonists of this invention have structure (Ib), wherein R,R₁, R₂ and R₃ are defined as above.

Further representative compounds of this invention include compounds ofgeneral formula (I) in which

-   -   R₂ and R₃ together with N form a 5-14 membered heterocyclic        group, which may be substituted by 1 to 3 R₁₀ groups; such R₁₀        groups are defined as above.

Depending upon the choice of X, the CRF receptor antagonists of thisinvention include compounds of formula (IIa) and (IIb), in which thegroup NR₂R₃ represents a 5-6 membered heterocyclic group, which may besubstituted by 1 to 3 R₈ groups.

In particular compounds of formula (IIa) and (IIb) are included

in which R₁, R and R₈ have the meanings as defined before.

Examples of such compounds are reported in the Experimental Part.

Even more preferred embodiments of the invention include, but are notlimited to, compounds of the formula (I), (Ia), (Ib), (IIa), (IIb),(IIIa), (IIIb):

wherein:

-   -   R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably        methyl or trifluoromethyl;    -   R₄ is hydrogen; and    -   R is an aryl group selected from: 2,4-dichlorophenyl,        2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl,        2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl,        2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl,        2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethyl,        2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl,        2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl,        2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl,        2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl,        2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl,        2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl,        2-trifluoromethyl-4-methoxyphenyl, 2-bromo4-isopropylphenyl,        2-methyl-4-cyanophenyl, 2-chloro-4-cyanophenyl,        4-methyl-6-dimethylaminopyridin-3-yl, 3,5-dichloro-pyridin-2-yl,        2,6-bismethoxy-pyridin-3-yl and        3-chloro-5-trichloromethyl-pyridin-2-yl.

Preferred compounds according to the invention are:

1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

3-methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile;

4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile;

6-methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

1-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-bismethoxy-pyridin-1,8]naphthyridine;

1-(4-methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

4-[1,3′]bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

In general, the compounds of structure (I) may be made according to theorganic synthesis techniques known to those skilled in this field, aswell as by the representative methods set forth in the Examples.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,and n have the meanings as previously defined for compounds of formula(I) unless otherwise stated.

Compounds of formula (IIa) may be conveniently prepared according to thefollowing Scheme 1:

in which

-   -   step a stands for conversion of the leaving group L, selected in        a group consisting from: halogen or reactive residue of        sulphonic acid (e.g. mesylate, tosylate), preferably chloride,        in the amino group of compounds (III), by reaction with the        suitable amine NR₂R₃ in basic conditions;    -   step b stands for reduction of the ester group with a suitable        reducing agent (such as DIBAl—H) to hydroxy group of compounds        (IV);    -   step c stands for oxidation of the hydroxy group with a suitable        oxidising agent (such as Dess-Martin periodinane) to aldehyde        group of compound (V);    -   step d stands for formation of the aldehyde group of        compounds (VII) by Wittig reaction in the usual conditions,        through formation of enol ether followed by acid hydrolysis        (step e);    -   step f stands for reduction of the aldehyde group with a        suitable reducing agent (such as NaBH₄) to hydroxy group of        compounds (VIII);    -   step g stands for conversion of the hydroxy group in the        suitable protecting group of compounds (IX)(such as TBS:        tert-butyldimethylsilyl);    -   step h stands for Buchwald reaction by coupling with the        suitable amine RNH₂;    -   step i stands for deprotection reaction to give the hydroxy        group of compounds (XI);    -   step l stands for intramolecular cyclisation by heating after        conversion of the hydroxy group of compounds (XI) in a suitable        leaving group (such as bromide, by reaction with CBr₄ and PPh₃)        to give the final compounds (IIa).

Alternatively, compounds of formula (IIa) may be conveniently preparedaccording to the following Scheme 2:

in which

-   -   step a′ stands for conversion of the hydroxy group in a suitable        leaving group L′ of compounds (XII), which, independently from        L, has the same definition (e.g mesylate, by reaction with MsCl        in Et₃N);    -   step b′ stands for conversion of L′ in the cyano derivative of        compounds (XIII) by reaction with, e.g. KCN in an aprotic        dipolar solvent, like DMF;    -   step c′ stands for reduction of the cyano group with a suitable        reducing agent agent (such as BH₃-THF) to the amino group of        compound (XIV);    -   step d′ stands for intramolecular cyclisation of compounds (XIV)        by heating in a suitable solvent (such as NMP) at high        temperature;    -   step e′ stands for reduction of the aldehyde group with a        suitable reducing agent (such as NaBH₄) to hydroxy group of        compounds (VIII);    -   step f′ corresponds to previous step h.

Compounds of formula (IIb) may be conveniently prepared according to thefollowing Scheme 3:

in which:

-   -   step a″ corresponds to previous step d;    -   step b″ corresponds to previous step e;    -   step c″ corresponds to previous step f;    -   step d″ corresponds to previous step g;    -   step e″ corresponds to previous step h;    -   step f″ corresponds to previous step i;    -   step g″ corresponds to previous step l;

Compounds of formula (II) are known compounds or may be preparedaccording to known methods in the literature.

Compounds of formula (IIIa) and (IIIb) may be prepared according to theprevious Schemes 1, 2 and 3, once prepared the heterocyclic reactiveresidue according to known methods to the skilled in the art.

Examples of suitable hydroxy protecting group include trihydrocarbylsilyl ethers such as the trimethylsilyl or t-butyldimethylsilyl ether.The hydroxyl protecting groups may be removed by well-known standardprocedures (such as those described in Protective Groups in OrganicChemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)).For example when Pg is a t-butyldimethylsilyl group, this may be removedby treatment with triethylamine trihydrofluoride.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation or evaporation of an appropriatesolvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

The subject invention also includes isotopically-labeled compounds,which are identical to those recited in formulas I and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Compounds of the present invention andpharmaceutically acceptable salts of said compounds that contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of the present invention. Isotopically-labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H, ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. ¹¹C and ⁸F isotopes are particularly useful in PET(positron emission tomography), and ¹²⁵I isotopes are particularlyuseful in SPECT (single photon emission computerized tomography), alluseful in brain imaging. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds offormula I and following of this invention can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

The CRF receptor antagonists of the present invention demonstrateactivity at the CRF receptor site including CRF 1 and CRF 2 receptorsand may be used in the treatment of conditions mediated by CRF or CRFreceptors.

The effectiveness of a compound as a CRF receptor antagonist may bedetermined by various assay methods. Suitable CRF antagonists of thisinvention are capable of inhibiting the specific binding of CRF to itsreceptor and antagonizing activities associated with CRF. A compound ofstructure (I) may be assessed for activity as a CRF antagonist by one ormore generally accepted assays for this purpose, including (but notlimited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88,1987) and Battaglia et al. (Synapse 1: 572,1987).

The CRF receptors-binding assay was performed by using the homogeneoustechnique of scintillation proximity (SPA). The ligand binds torecombinant membrane preparation expressing the CRF receptors which inturn bind to wheatgerm agglutinin coated SPA beads. In the ExperimentalPart will be disclosed the details of the experiments.

With reference to CRF receptor binding affinities, CRF receptorantagonists of this invention have a Ki less than 10 μm.

Compounds of the invention are useful in the treatment of centralnervous system disorders where CRF receptors are involved. In particularin the treatment or prevention of major depressive disorders includingbipolar depression, unipolar depression, single or recurrent majordepressive episodes with or without psychotic features, catatonicfeatures, melancholic features, atypical features or postpartum onset,the treatment of anxiety and the treatment of panic disorders. Othermood disorders encompassed within the term major depressive disordersinclude dysthymic disorder with early or late onset and with or withoutatypical features, neurotic depression, post traumatic stress disordersand social phobia; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; schizoaffective disorder of the depressed type; andadjustment disorder with depressed mood. Major depressive disorders mayalso result from a general medical condition including, but not limitedto, myocardial infarction, diabetes, miscarriage or abortion, etc.

Compounds of the invention are also useful in the treatment orprevention of schizophrenic disorders including paranoid schizophrenia,disorganised schizophrenia, catatonic schizophrenia, undifferentiatedschizophrenia, residual schizoprenia.

Compounds of the invention are useful as analgesics. In particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful for the treatment ofdysfunction of appetite and food intake and in circumstances such asanorexia, anorexia nervosa and bulimia.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of cognitive disorders. Cognitive disorders include dementia,amnestic disorders and cognitive disorders not otherwise specified.

Furthermore compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds), or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of cocaine, sedative ipnotic,amphetamine or amphetamine-related drugs (e.g. dextroamphetamine,methylamphetamine) addiction or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease (IBD)and non-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

Compounds of the invention are of particular use in the treatment ofgastrointestinal disorders such as irritable bowel syndrome (IBS); skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

Compounds of the invention are useful for the treatment of neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia,anoxia, perinatal asphyxia cardiac arrest.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by CRF.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofcondition mediated by CRF, comprising administration of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or a solvate thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Thus for parenteral administration a daily dose will typically be in therange of 1 to about 100 mg, preferably 1 to 80 mg per day. For oraladministration a daily dose will typically be within the range 1 to 300mg e.g. 1 to 100 mg.

EXAMPLES

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus andare uncorrected. All temperatures refers to ° C. Infrared spectra weremeasured on a FT-IR instrument. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), doublets (d), doublets of doublets (dd), triplets (t),quartets (q) or multiplets (m). Column chromathography was carried outover silica gel (Merck AG Darmstaadt, Germany). The followingabbreviations are used in text: EtOAc=ethyl acetate, cHex=cyclohexane,CH₂Cl₂=dichloromethane, Et₂O=dietyl ether, DMF=N,N′-dimethylformamide,DIPEA=N,N-diisopropylethylamine, DME=ethylene glycol dimethyl ether,MeOH=methanol, Et₃N=triethylamine, TFA=trifluoroacetic acid,THF=tetrahydrofuran, DIBAL-H=diisobutylaluminium hydride,DMAP=dimethylaminopyridine, LHMDS=lithiumhexamethyldisilazane; Tlcrefers to thin layer chromatography on silica plates, and dried refersto a solution dried over anhydrous sodium sulphate; r.t. (RT) refers toroom temperature.

Intermediate 1

2,4-Dichloro-6-methyl-nicotinic acid ethyl ester

The title compound was prepared according to an already publishedprocedure: Mittelbach, Martin; Synthesis, 1988, 6, p. 479-80.

Intermediate 2

2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-nicotinic acid ethylester

To a solution of 2-(1H-pyrazol-3-yl)-1,3-thiazole (7.71 g, 1.05 eq) inanh. DMF (61 mL), at 0° C., under N₂, was added NaH 60% in mineral oil(2.03 g, 1.05 eq) and the reaction mixture was stirred for 10 min. at 0°C. and then for 1 hr at room temperature. Intermediate 1 (11.34 g, 48.0mmol) was then added as a solution in anh. DMF (35 mL) at 0° C. and theresulting solution was heated at 110° C. for 3 hr. The reaction was thenquenched with water, extracted with EtOAc, washed with brine, dried overanh. Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give7.02 g of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 7.91 (d, 1H), 7.91 (d, 1H), 7.41 (d, 1H), 7.31 (s,1H), 7.18 (d, 1H), 4.50 (q, 2H), 2.78 (s, 3H), 1.25 (t, 3H).

MS (m/z): 349 [MH]⁺.

Intermediate 3

[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-methanol

To a solution of intermediate 2 (1.5 g, 4.3 mmol) in anh. CH₂Cl₂ (30mL), at −78° C., under N₂, was added DIBAl—H 1.0 M in cyclohexane (12.9mL, 3.0 eq). The reaction mixture was stirred for 1 hr at −78° C. andthen for 1 hr at room temperature. The reaction was then quenched with asaturated solution of Rochelle's salt, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 1:1) to give 1.02 g of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 8.05 (d, 1H), 7.90 (d, 1H), 7.40 (d, 1H), 7.25 (s,1H), 7.10 (d, 1H), 4.65 (S, 2H), 4.0 (bs, 1H), 2.60 (s, 3H).

MS (m/z): 307 [M]⁺.

Intermediate 4

2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine-3-carbaldehyde

To a solution of intermediate 3 (150 mg, 0.5 mmol) in anh. CH₂Cl₂ (5mL), at room temperature, under N₂, was added the Dess Martinperiodinane (237 mg, 1.12 eq) and the reaction mixture was stirred for 1hr at room temperature. The reaction was then quenched with a solutionof 0.5 g of sodium thiosulfate dissolved in a saturated solution ofsodium bicarbonate, extracted with EtOAc, washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 1:1) to give124 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 10.4 (s, 1H), 8.0-7.9 (2d, 2H), 7.40 (2d, 2H), 7.10(s, 1H), 2.70 (s, 3H).

MS (m/z): 305 [MH]⁺.

Intermediate 5

2-Chloro-3-(2-methoxy-vinyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

To a solution of (methoxymethyl)-triphenylphosphonium chloride (4.24 g,3 eq) in anh. THF (20 mL), at 0° C., under N₂, was added n-BuLi 1.6 M incyclohexane (7.73 ml, 12.37 mmol) and the reaction mixture was broughtto room temperature and then stirred for 15 min. A solution ofintermediate 4 (1.25 g, 4.1 mmol) in anh. THF (15 mL) was then added andthe reaction was stirred at room temperature for 1.5 hr. The reactionwas then quenched with water, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc4:1) to give 961 mg of the title compound as a white solid (E:Z=3:2mixture, used as such in the next step).

NMR (¹H, CDCl₃) principal E product: δ 7.90 (m, 1H), 7.83 (m, 1H), 7.38(m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.51 (d, 1H), 5.63 (d, 1H), 3.64(s, 3H), 2.60 (s, 3H).

MS (m/z): 333 [MH]⁺.

Intermediate 6

[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-acetaldehyde

To a solution of intermediate 5 (936 mg, 2.8 mmol) in anh. THF (15 mL)was added 6N HCl (21 ml, 45 eq) and the reaction mixture was stirred atroom temperature for 15 hr. The reaction was then quenched with sat. aq.NaHCO₃ until pH=7, extracted with EtOAc, washed with brine, dried overanh. Na₂SO₄, filtered and concentrated in vacuo to give 893 mg of thetitle compound as a white solid, which was used in the next step withoutfurther purification.

NMR (¹H, CDCl₃): δ 9.80 (s, 1H), 7.90-7.80 (2d, 2H), 7.70 (d, 1H), 7.20(d, 1H), 7.0 (s, 1H), 4.25 (s, 2H), 2.70 (s, 3H).

MS (m/z): 319 [MH]⁺.

Intermediate 7

2-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethanol

To a solution of intermediate 6 (903 mg, 2.84 mmol) in anh. MeOH (10 mL)were added CeCl₃ (700 mg, 1 eq) and NaBH₄ (107 mg, 1 eq) and thereaction mixture was stirred at room temperature for 5 min. The reactionwas then quenched with water, extracted with ethyl acetate, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo togive 848 mg of the title compound as a white solid, which was used inthe next step without further purification.

NMR (¹H, CDCl₃): δ 8.00 (m, 2H), 7.50 (d, 1H), 7.20 (m, 2H), 4.25 (t,2H), 3.20 (t, 2H), 2.70 (s, 3H).

MS (m/z): 321 [MH]⁺.

Intermediate 8

3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

To a solution of intermediate 7 (840 mg, 2.6 mmol) in anh. CH₂Cl₂ (10mL) were added 2,6-lutidine (0.67 ml, 2.2 eq) andtert-butyldimethylsilyl triflate (0.89 ml, 1.5 eq) and the reactionmixture was stirred at room temperature for 15 hr. The reaction was thenquenched with an aqueous solution of saturated NH₄Cl, extracted withEtOAc, washed with brine, dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The product was purified by flash chromatography(silica gel, cHex/EtOAc 3:2) to give 950 mg of the title compound as acolorless oil.

NMR (¹H, CDCl₃): δ 8.20 (d, 1H), 7.75 (d, 1H), 7.35 (d, 1H), 7.00 (m,2H), 4.00 (t, 2H), 3.05 (t, 2H), 2.55 (s, 3H), 0.80 (s, 9H), −0.10 (s,6H).

MS (m/z): 435 [MH]⁺.

Intermediate 9

(2,4-Bis-trifluoromethyl-phenyl)-[3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-amine

To a solution of intermediate 8 (240 mg, 0.553 mmol) in anh. DME (1 mL)were added Pd₂(dba)₃ (51 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (60 mg, 0.3 eq), K₃PO₄ (317mg, 3 eq) and 2,4-bis(trifluoromethyl) aniline (0.17 ml, 2 eq) and thereaction mixture was submitted to microwave irradiation (150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The productwas purified by flash chromatography (silica gel, cHex/EtOAc 9:1) togive 180 mg of the title compound as a colorless oil.

NMR (¹CDCl₃): δ 8.55 (d, 1H), 8.20 (bs, 1H), 7.90 (d, 1H), 7.80 (m, 2H),7.65 (dd, 1H), 7.40 (d, 1H), 7.05 (d, 1H), 6.85 (s, 1H), 4.20 (t, 2H),2.90 (t, 2H), 2.60 (s, 3H), 0.80 (s, 9H), 0.10 (s, 6H).

MS (m/z): 628 [MH]⁺.

Intermediate 10

2-[2-(2,4-Bis-trifluoromethyl-phenylamino)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethanol

To a solution of intermediate 9 (240 mg, 0.38 mmol) in anh. THF (5 mL)was added Et₃N.3HF (0.187 ml, 3 eq) and the reaction mixture was stirredfor 15 hr at room temperature. The reaction was then quenched with anaqueous solution of saturated NH₄Cl, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo. Theproduct was purified by flash chromatography (silica gel, cHex/EtOAc1:1) to give 180 mg of the title compound as a colorless oil.

NMR (¹H, CDCl₃): δ 8.45 (bs, 1H), 8.20 (d, 1H), 7.85 (d, 1H), 7.85 (2d,2H), 7.65 (dd, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.85 (s, 1H), 4.20 (t,2H), 2.85 (t, 2H), 2.50 (s, 3H).

MS (m/z): 514 [MH]⁺.

Intermediate 11

Methanesulfonic acid2-chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-ylmethylester

To a solution of intermediate 3 (308 mg, 1.01 mmol) in anh. CH₂Cl₂ (2.5mL), at −25° C., under N₂, was added Et₃N (280 μL, 2 eq) and CH₃SO₂Cl(120 μL, 1.5 eq). The reaction mixture was stirred at −25° C. for 2 hrand than at −5° C. for another 2 hr. The reaction mixture was dilutedwith water and extracted with CH₂Cl₂. The combined organic extracts weredried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc6:4→1:1) to give 88 mg of the title compound as a colourless oil.

NMR (¹H, CDCl₃): δ 7.90 (d, 1H), 7.87 (d, 1H), 7.39 (d, 1H), 7.34 (s,1H), 7.14 (d, 1H), 5.5 (s, 2H), 3.0 (s, 3H), 2.78 (s, 3H).

MS (m/z): 385 [MH]⁺, Cl

Intermediate 12

[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-acetonitrile

To a solution of intermediate 11 (88 mg, 0.229 mmol) in anh. DMF (2.5mL), at 0° C., under N₂, was added KCN (15 mg, 1 eq). The reactionmixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with water and 1M NaOH and extracted with Et₂O. The combinedorganic extracts were dried over anh. Na₂SO₄, filtered and concentratedin vacuo. The title compound was obtained as a yellow solid (60 mg) andwas used in the next step without further purification.

NMR (¹H, CDCl₃): δ 7.92 (d, 1H), 7.91 (d, 1H), 7.41 (d, 1H), 7.31 (s,1H), 7.18 (d, 1H), 3.99 (s, 2H), 2.78 (s, 3H).

MS (m/z): 316 [MH]⁺, Cl

Intermediate 13

2-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethylamine

To a solution of intermediate 12 (810 mg, 2.571 mmol) in anh. THF (6mL), at r.t., under N₂, was added BH₃.THF (10.3 mL, 4 eq). The reactionmixture was stirred at reflux temperature for 2 hr. The reaction mixturewas concentrated in vacuo and diluted with MeOH. 1M HCl in Et₂O (7.7 μL,3 eq) was added at r.t. and the solution was stirred at reflux for 2 hr.The reaction mixture was diluted with water and basified with 1M NaOH topH=12. The crude product was purified by flash chromatography (silicagel CH₂Cl₂/MeOH 6:4). The title compound was obtained as a pale yellowsolid (690 mg).

NMR (¹H, CDCl₃): δ 8.42 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.48 (s,1H), 7.07(d, 1H), 2.81 (m, 4H), 2.51 (s, 3H), 2.0 (bs, 2H).

MS (m/z): 320 [MH]⁺, Cl

Intermediate 14

6-Methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

To a solution of intermediate 13 (640 mg, 2.01 mmol) in dryN-methylpyrrolidinone (13 mL), at r.t., under N₂, was added Et₃N (1.12mL, 4 eq). The reaction mixture was stirred at 110° C. for 7 hr. Thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, CH₂Cl₂/MeOH 98:2). The title compound wasobtained as white solid (187 mg).

NMR (¹H, CDCl₃): δ 7.98 (d, 1H), 7.89 (d, 1H), 7.35 (d, 1H), 7.06 (d,1H), 4.65 (bs, 1H), 3.72 (t, 2H), 3.48 (t, 2H), 2.42 (s, 3H)

MS (m/z): 284 [MH]⁺

Intermediate 15

2-Chloro-3-(3-methoxy-allyl)-6-methyl-4-(3-thiazol-2-1-pyrazol-1-yl)-pyridine

To a stirred suspension of (methoxy-methyl)triphenylphosphonium chloride(833 mg, 3eq.) in anh. THF (4 mL) was added dropwise, at 0° C., underN₂, n-BuLi in hexanes 1.6 M (1.50 ml, 3 eq). The reaction mixture wasstirred at r.t. for 15 rnin before a solution of intermediate 6 (258 mg,I eq) in anh. THF (3 ml) was added. The reaction mixture was stirred for1.5 hr. The mixture was quenched with water and extracted with EtOAc.The combined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated to dryness in vacuo. The crude product was purified byflash chromatography (silica gel, cHex/EtOAc 8:2) to give 220 mg of thetitle compound as an unseparable mixture of trans and cis (60/40) vinylether (yellow oil, 78%)

NMR (¹H, CDCl₃): δ 7.88 (d, 1H), 7.79 (d, 1H), 7.36 (d, 1H), 7.19 (s,1H), 7.08 (d, 1H), 6.31 (d, 1H), 4.90 (m, 1H), 3.44 (d, 2H), 3.48 (s,3H), 2.57 (s, 3H).

MS (m/z): 347 [MH]⁺, 1 Cl

Intermediate 16

3-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propionaldehyde

To a solution of intermediate 15 (370 mg, 1.07 mmol) in THF (5 mL) wasadded HCl 6 N (12 ml, 67.5 eq) and the reaction mixture was stirred for13 hr at r.t. A solution of NaHCO₃ was added to the reaction mixtureuntil pH=7 was reached and the aqueous phase was extracted with EtOAc.The combined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated to dryness in vacuo. The crude title compound (335 mg) wasused in the following step without further purification.

NMR (¹H, CDCl₃): δ 9.84 (s, 1H), 7.84 (d, 1H), 7.75 (d, 1H), 7.30 (d,1H), 7.06 (d, 1H), 7.05 (s, 1H), 3.10-3.30 (m, 4 H), 2.55 (s, 3H).

MS (m/z): 333 [M+1]⁺, 1Cl

Intermediate 17

3-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propan-1-ol

To a solution of intermediate 16 (335 mg, 1 mmol) in anh. CH₃OH (5 mL)were added CeCl₃ (247 mg, 1 eq) and NaBH₄ (38 mg, 1 eq) at r.t., underN₂. The reaction mixture was stirred for 20 min. The solvent was removedin vacuo and the residue was redissolved in EtOAc/H₂O and the layerswere separated. The aqueous layer was extracted with EtOAc, and thecombined organic extracts were dried over anh. Na₂SO₄, filtered, andconcentrated in vacuo. Purification (silica gel, cHex/EtOAc 8:2) of thecrude afforded 277.4 mg of the title compound as a clear oil.

NMR (¹H, CDCl₃): δ 7.90 (d, 1H), 7.76 (d, 1H), 7.36 (d, 1H), 7.12 (s,1H), 7.07 (d, 1H), 3.70 (m, 2H), 2.90 (t, 2H), 2.58 (s, 3H), 2.20 (bt,1H), 2.04 (m, 2H).

MS (m/z): 335 [M+1]⁺, 1Cl

Intermediate 18

3-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-2-chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

To a solution of intermediate 17 (277.4 mg, 0.83 mmol) in anh. DMF (7mL) was added imidazole (621 mg, 11 eq), tert-butyldimethylsilylchloride (350 mg, 2.8 eq) and a catalytic amount of DMAP at 0° C. underN₂. The reaction mixture was stirred at room temperature for 2 hr. Thena saturated aqueous solution of NH₄Cl was added to the reaction mixtureand it was extracted with EtOAc. The combined organic extracts weredried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc7:3) to give 347 mg of the title compound as a yellow oil.

NMR (¹H, CDCl₃): δ 7.89 (d, 1H), 7.81 (d, 1H), 7.34 (d, 1H), 7.20 (s,1H), 7.08 (d, 1H), 3.66 (t, 2H), 2.86 (m, 2H), 2.57 (s, 3H), 1.89 (m,2H), 0.86 (s, 9H), −0.006 (s, 6H).

MS (m/z): 449 [M]⁺, 1Cl

Intermediate 19

(2,4-Bis-trifluoromethyl-phenyl)-[3-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-amine

To a vial containing Pd(dba)₃ (17 mg, 0.1 eq),2-(Dicyclohexylphosphino)-2′-methylbiphenyl (20 mg, 0.3 eq) and K₃PO₄(103 mg, 2.7 eq), at r.t., under N₂, were added a solution ofintermediate 18 (80 mg, 0.18 mmol) in anh. DME (0.5 mL) and a solutionof 2,4-bis(trifluoromethyl)aniline (82 mg, 2 eq) in dry DME (0.5 mL).The reaction mixture was submitted to microwave irradiation five times(3×10 min+30 min+60 min) with these observed parameters: P=110 W; T=100°C., p=18 psi. The solution was diluted with water and extracted withEtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated to dryness in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/Et₂O 7:3) to give 49mg of the title compound as a yellow oil.

NMR (¹H, CDCl₃): δ 8.58 (d, 1H), 7.89 (d, 1H), 7.85 (d, 1H), 7.77 (dd,1H), 7.76 (d, 1H), 7.34 (d, 1H), 7.23 (bs, 1H), 7.08 (d, 1H), 6.86 (s,1H), 3.67 (t, 2H), 2.69 (m, 2H), 2.3 (s, 3H), 1.90 (m, 2H), 0.8 (s, 9H),−0.02 (s, 6H).

MS (m/z): 642 [M+1]⁺

Intermediate 20

3-[2-(2,4-Bis-trifluoromethyl-phenylamino)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propan-1-ol

To a solution of intermediate 19 (60 mg, 0.094 mmol) in anh. THF (2 mL)was added TEA-3HF (0.046 mL, 3 eq). The reaction mixture was stirred atroom temperature for 12 hr. Then a saturated solution of NH₄Cl was addedto the reaction mixture and it was extracted with EtOAc. The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, cHex/EtOAc 1:1) to give 34.6 mg of the title compound as a whitesolid.

NMR (¹H, CDCl₃): δ 8.62 (d, 1H), 7.90 (d, 1H), 7.85 (bs, 1H), 7.76 (dd,1H), 7.7 (d, 1H), 7.37 (bs, 1H), 7.36 (d, 1H), 7.07 (d, 1H), 6.83 (s,1H), 3.73 (t, 2H), 2.73 (t, 2H), 2.52 (s, 3H), 2.04(m, 2H).

MS (m/z): 528 [M+1]⁺

Intermediate 21

2,4-Bis-trifluoromethyl-phenyl)-[3-(3-bromo-propyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-amine

To a solution of intermediate 20 (34.6 mg, 0.066 mmol) in anh. CH₂Cl₂ (1mL) was added CBr₄ (44 mg, 2 eq) and PPh₃ (34 mg, 2 eq). The reactionmixture was stirred at room temperature for 1 hr. Then a saturatedaqueous solution of NaHCO₃ was added to the reaction mixture and it wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give25.7 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 8.6 (d, 1H), 7.90 (d, 1H), 7.87 (d, 1H), 7.77 (m,1H), 7.37 (d, 1H), 7.15 (bs, 1H), 7.10 (d, 1H), 6.84 (s, 1H), 3.47 (t,2H), 2.78 (m, 2H), 2.52 (s, 3H), 2.3 (m, 2H).

MS (m/z): 590 [M]⁺, 1Br; 510 [M-Br]⁺

Intermediate 22

4-[3-[2-(tert-Butyl-dimethyl-silayloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-methyl-benzonitrile

To a solution of intermediate 8 (186 mg, 0.43 mmol) in anh. DME (1 mL)were added Pd₂(dba)₃ (39 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (47 mg, 0.3 eq), K₃PO₄ (246mg, 2.6 eq) and 3-methyl-4-amino benzonitrile (113 mg, 2 eq) and thereaction mixture was submitted to microwave irradiation (150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc8:2) to give 61 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 8.30 (d, 1H), 8.06 (bs, 1H), 7.89 (d, 1H), 7.78 (d,1H), 7.46 (dd, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 6.81 (s,1H), 4.34 (m, 2H), 2.82 (t, 2H), 2.56 (s, 3H), 2.36 (s, 3H), 0.85 (s,9H), 0.02 (s, 6H).

MS (m/z): 531 [MH]⁺.

Intermediate 23

4-[3-(2-Hydroxy-ethyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-methyl-benzonitrile

To a solution of intermediate 22 (61 mg, 0.115 mmol) in anh. THF (2 mL)was added Et₃N.3HF (0.056 ml, 3 eq) and the reaction mixture was stirredfor 15 hr at room temperature. The reaction was then quenched with anaqueous solution of saturated NH₄Cl, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo. Theproduct was purified by flash chromatography (silica gel, cHex/EtOAc1:1) to give 46 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 8.39 (bs, 1H), 8.14 (d, 1H), 7.90 (d, 1H), 7.79 (d,1H), 7.46 (m, 2H), 7.36 (d, 1H), 7.09 (d, 1H), 6.82 (s, 1H), 4.34 (m,2H), 2.83 (t, 2H), 2.54 (s, 3H), 2.34 (s, 3H).

MS (m/z): 417 [MH]⁺.

Intermediate 24

4-[3-(2-Hydroxy-ethyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-trifluoromethyl-benzonitrile

To a solution of intermediate 8 (106 mg, 0.244 mmol) in anh. DME (1 mL)were added Pd₂(dba)₃ (22 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (27 mg, 0.3 eq), K₃PO₄ (140mg, 2.7 eq) and 3-trifluoromethyl-4-amino benzonitrile (91 mg, 2 eq) andthe reaction mixture was submitted to microwave irradiation (150 W, 100°C., 60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The productwas purified by flash chromatography (silica gel, cHex[EtOAc 8:2) andthe isolated product containing some unreacted aniline was used in thenext step without further purification.

To a solution of the mixture obtained above (120 mg) in anh. THF (5 mL)was added Et₃N.3HF (0.063 ml, 3 eq) and the reaction was stirred for 15hr at room temperature. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The productwas purified by flash chromatography (silica gel, cHex[EtOAc 1:1). togive 40 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 8.81 (bs, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.87 (d,1H), 7.79 (d, 1H), 7.68 (dd, 1H), 7.37 (d, 1H), 7.17 (d, 1H), 6.92 (s,1H), 4.26 (q, 2H), 2.87 (t, 2H), 2.54 (s, 3H), 2.63 (t, 1H).

MS (m/z): 471 [MH]⁺.

Intermediate 25

[3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-(2-methyl-4-trifluoromethoxy-phenyl)-amine

To a solution of intermediate 8 (110 mg, 0.253 mmol) in anh. DME (1 mL),at r.t., under N₂, were added Pd₂(dba)₃ (23 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (28 mg, 0.3 eq), K₃PO₄ (145mg, 2.7 eq) and 2-methyl-4-trifluoromethyl aniline (97 mg, 2 eq) and thereaction mixture was sumitted to microwave irradiation(150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The product waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give 80mg of the title compound as a yellow oil.

NMR (¹H, CDCl₃): δ 8.05 (d, 1H), 7.83 (bs, 1H), 7.78 (d, 1H), 7.7 (d,1H), 7.46 (dd, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 6.81 (s,1H), 4.34 (m, 2H), 2.82 (t, 2H), 2.56 (s, 3H), 2.36 (s, 3H), 0.85 (s,9H), 0.023 (s, 6H).

MS (m/z): 590 [MH]⁺.

Intermediate 26

2-[6-Methyl-2-(2-methyl-4-trifluoromethoxy-phenylamino)-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethanol

To a solution of intermediate 25 (80 mg, 0.135 mmol) in anh. THF (2 mL)was added Et₃N.3HF (66 μL, 8 eq) and the reaction mixture was stirredfor 15 hr at room temperature. The reaction was then quenched with anaqueous solution of saturated NH₄Cl, extracted with EtOAc, washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theproduct was purified by flash chromatography (silica gel, cHex/EtOAc 1:1) to give 48 mg of the title compound as a colorless oil.

NMR (¹H, CDCl₃): δ 7.91 (bs, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.65 (d,1H), 7.30 (d, 1H), 7.15-6.95 (m, 3H), 6.65 (s, 1H), 4.34 (m, 2H), 2.83(t, 2H), 2.54 (s, 3H), 2.34 (s, 3H).

Example 1

Synthesis of representative compounds of structure (IIIa)

Example 1-11-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

To a solution of intermediate 10 (40 mg, 0.078 mmol) in anh. CH₂Cl₂ (2mL), at r.t., under N₂, were added CBr₄ (52 mg, 2 eq) and PPh₃ (41 mg, 2eq) and the reaction mixture was stirred for 3 hr. The reaction was thenquenched with an aqueous solution of saturated NaHCO₃, extracted withEtOAc, washed with brine, dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The product was purified by flash chromatography(silica gel, cHex/EtOAc 2:1) to give 18 mg of the title compound as awhite solid.

Alternatively:

Example 1-11-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

To a mixture of tris(dibenzylidenacetone)palladium(0) (3.2 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (3.8 mg, 0.3 eq) and K₃PO₄(20 mg, 2.8 eq) in a crimp cap microwave vial was added a solution ofintermediate 14 (10 mg, 0.035 mmol) and2,4-bis(trifluoromethyl)-bromobenzene (6 μL, 1 eq) in anh. DME (1 mL),under N₂. The reaction mixture was submitted to microwave irradiationfor two cycles (2×10 min) with these observed parameters: P=150 W;T=100° C., p=60 psi Then water (1 mL) was added and the product wasextracted with EtOAc. The combined organic extracts were washed withsat. aq. NaCl (5 mL) and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated to give a crude product, which waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3). The titlecompound was obtained as a colourless oil (1 mg, 0.002 mmol).

Example 1-23-Methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile

To a solution of intermediate 23 (44 mg, 0.106 mmol) in anh. CH₂Cl₂ (2mL) were added CBr₄ (71 mg, 2 eq) and PPh₃ (60 mg, 2 eq) and thereaction mixture was stirred for 3 hr at room temperature. The reactionwas then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 4:1) to give 18 mg of the titlecompound as a white solid.

Example 1-34-[6-Methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile

To a solution of intermediate 24 (40 mg, 0.085 mmol) in anh. CH₂Cl₂ (2mL) were added CBr₄ (56 mg, 2 eq) and PPh₃ (45 mg, 2 eq) and thereaction mixture was stirred for 3 hr at room temperature. The reactionwas then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 2:1) to give 13 mg of the titlecompound as a white solid.

Example 1-46-Methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

To a solution of intermediate 26 (48 mg, 0.101 mmol) in anh. CH₂Cl₂ (2mL) were added CBr₄ (66 mg, 2 eq) and PPh₃ (53 mg, 2 eq) and thereaction mixture was stirred for 3 hr at room temperature. The reactionwas then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 8:2) to give 10 mg of the titlecompound as a white solid.

Example 1-51-(4-Methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

To a solution of intermediate 28 (31 mg, 0.075 mmol, 1 eq.) in DCM dry(5 ml), was added CBr₄ (53 mg, 0.16 mmol, 2.1 eq.) andtriphenylphosphine (42 mg, 0.16 mmol, 2.1 eq.) under N₂. The reactionmixture was stirred at RT for 15 hrs. Then water (10 ml) was added andthe aqueous phase was extracted with EtOAc (20 ml). The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The crude waspurified by flash chromatography (Eluents: cyclohexane/ethyl acetate7:3) to give 5.2 mg of VSAF/6274/4/1 as a colorless oil.

Example 1-61-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

Prepared analogously to example 1-1 using 4-(1H-pyrazol-3-yl)-morpholine(J. Org. Chem., 1984, 269-276) instead of 2-(1H-pyrazol-3-yl)-thiazolein the preparation of intermediate 2.

Example 1-71-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

Prepared analogously to example 1-1 using 2-(1H-Pyrazol-3-yl)-pyridine(commercially available) instead of 2-(1H-pyrazol-3-yl)-thiazole in thepreparation of intermediate 2.

Example 1-84-[1,3′]Bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

Prepared analogously to example 1-1 using 1′H-[1,3′]bipyrazolyl (from1H-pyrazol-3-ylamine: J. Heterocycl. Chem., 1983, 1629-1639; then J.Heterocycl. Chem., 1989, 733-738) instead of2-(1H-pyrazol-3-yl)-thiazole in the preparation of intermediate 2.

All the analytical data are set forth in the following Table 1-1.

TABLE 1-1 Cpd. No. R R₁ R₂—R₃— Analytical Data 1-1 2,4-bistrifluoro-methylphenyl CH₃

NMR (¹H, DMSO): δ 8.64 (d, 1H), 8.17 (dd, 1H), 8.13 (d, 1H), 7.94 (d,1H), 7.84 (d, 1H), 7.80 (d, 1H), 7.09 (m, 2H), 3.97 (t, 2H), 3.56 (t,2H), 2.24 (s, 3H). MS (m/z): 496 [MH]⁺. 1-2 2-methyl-4-cyano CH₃

NMR (¹H, DMSO): δ 8.02 (d, 1H), 7.90 (d, 1H), 7.59 (d, 1H), 7.53 (dd,1H), 7.41 (d, 1H), 7.38 (d, 1H), 6.76 (s, 1H), 4.04 (t, 2H), 3.62 (t,2H), 2.41 (s, 3H), 2.33 (s, 3H). MS (m/z): 399 [MH]⁺. 1-32-trifluoromethyl- 4-cyano CH₃

NMR (¹H, CDCl₃): δ 8.00 (m, 2H), 7.9-7.8 (d+d, 2H), 7.65 (d, 1H), 7.35(d, 1H), 7.10 (d, 1H), 6.80 (s, 1H), 4.00 (t, 2H), 3.60 (t, 2H), 3.56(t, 2H), 2.40 (s, 3H). MS (m/z): 453 [MH]⁺. 1-4 2-methyl-4-tri-fluoromethoxy CH₃

NMR (¹H, DMSO): δ 8.01 (d, 1H), 7.89 (d, 1H), 7.5 (d, 1H), 7.45 (dd,1H), 7.20 (d, 1H), 7.1 (dd, 2H), 6.65 (s, 1H), 3.9 (t, 2H), 3.56 (t,2H), 2.32 (s, 3H), 2.25 (s, 3H). MS (m/z): 458.5 [MH]⁺. 1-52-methyl-4-methoxy CH₃

NMR (¹H, CDCl₃): δ 7.97 (d, 1H), 7.86 (d, 1H), 7.33 (d, 1H), 7.17 (d,1H), 7.10 (d, 1H), 6.78 (m, 2H), 6.61 (s, 1H), 3.90 (t, 2H), 3.80 (s,3H), 3.52 (t, 2H), 2.34 (s, 3H), 2.23 (s, 3H). MS (m/z): 404 [MH]⁺

Example 2

Synthesis of representative compounds of structure (IIIb)

All the analytical data are set forth in the following Table 2-1.

Example 2-11-(2,4-Bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

To a solution of intermediate 21 (24.8 mg, 0.042 mmol) in anh.N-metylpyrrolidinone (2 mL) was added Et₃N (12 μL, 2 eq) under N₂. Thereaction mixture was submitted to microwave irradiation for 10 min withthese observed parameters: P=90 W; T=99° C., p=6 psi. Then a saturatedaqueous solution of NH₄Cl was added to the reaction mixture and theaqueous phase was extracted with EtOAc. The combined organic extractswere washed with a saturated solution of NH₄Cl (3×), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bySCX Column (Eluents: CH₂Cl₂, MeOH and a solution of conc. NH₄OH in MeOH(25%) to elute the desired product) to give 18.4 mg of the titlecompound as a white foam. TABLE 2-1 Cpd. No. R R₁ R₂—R₃— Analytical Data2-1 2,4-bistrifluoro- methylphenyl CH₃

NMR (¹H, CDCl₃): δ 8.02 (bs, 1H), 7.89 (d, 1H), 7.88 (dd, 1H), 7.74 (d,1H), 7.46 (d, 1H), 7.35 (d, 1H), 7.06 (d, 1H), 6.59 (s, 1H), 3.66 (bm,2H), 2.97 (bm, 1H), 2.85 (bm, 1H), 2.18 (s, 3H), 2.09 (bm, 1H), 2.04(bm, 1H). MS (m/z): 510 [M+ 1]⁺

Example 3

CRF Binding Activity

CRF binding affinity has been determined in vitro by the compounds'ability to displace ¹²⁵I-oCRF and ¹²⁵I-Sauvagine for CRF1 and CRF2 SPA,respectively, from recombinant human CRF receptors expressed in ChineseHamster Ovary (CHO) cell membranes. For membrane preparation, CHO cellsfrom confluent T-flasks were collected in SPA buffer (HEPES/KOH 50 mM,EDTA 2 mM; MgCl₂ 10 mM, pH 7.4.) in 50 mL centrifuge tubes, homogenizedwith a Polytron and centrifuged (50,000 g for 5 min at 4° C.: Beckmancentrifuge with JA20 rotor). The pellet was resuspended, homogenized andcentrifuged as before.

The SPA experiment has been carried out in Optiplate by the addition of100 μL the reagent mixture to 1 μL of compound dilution (100% DMSOsolution) per well. The assay mixture was prepared by mixing SPA buffer,WGA SPA beads (2.5 mg/mL), BSA (1 mg/mL) and membranes (50 and 5 μg ofprotein/mL for CRF1 and CRF2 respectively) and 50 pM of radioligand.

The plate was incubated overnight (>18 hrs) at room temperature and readwith the Packard Topcount with a WGA-SPA ¹²⁵I counting protocol.

Example 4

CRF Functional Assay

Compounds of the invention were characterised in a functional assay forthe determination of their inhibitory effect. Human CRF-CHO cells werestimulated with CRF and the receptor activation was evaluated bymeasuring the accumulation of cAMP.

CHO cells from a confluent T-flask were resuspended with culture mediumwithout G418 and dispensed in a 96-well plate, 25,000 c/well, 100μL/well and incubated overnight. After the incubation the medium wasreplaced with 100 μL of cAMP IBMX buffer warmed at 37° C. (5 mM KCl, 5mM NaHCO₃, 154 mM NaCl, 5 mM HEPES, 2.3 mM CaCl₂, 1 mM MgCl₂; 1 g/Lglucose, pH 7.4 additioned by 1 mg/mL BSA and 1 mM IBMX) and 1 μL ofantagonist dilution in neat DMSO. After 10 additional minutes ofincubation at 37° C. in a plate incubator without CO2, 1 μL of agonistdilution in neat DMSO was added. As before, the plate was incubated for10 minutes and then cAMP cellular content was measured by using theAmersham RPA 538 kit.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. Compounds of formula (I) including stereoisomers, prodrugs andpharmaceutically acceptable salts or solvates thereof

R is aryl or heteroaryl, each of which may be substituted by 1 to 4groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R₅, nitro,—NR₆R₇, cyano, and a group R₈; R₁ is hydrogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen,NR₆R₇ or cyano; R₂ is hydrogen, C3-C7 cycloalkyl, or a group R₉; R₃ isC3-C7 cycloalkyl, or a group R₉; or R₂ and R₃ together with N form a5-14 membered heterocycle, which may be substituted by 1 to 3 R₁₀groups; R₄ is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R₅ isa C1-C4 alkyl, —OR₆ or —NR₆R₇; R₆ is hydrogen or C1-C6 alkyl; R₇ ishydrogen or C1-C6 alkyl; R₈ is a 5-6 membered heterocycle, which may besaturated or may contain one to three double bonds, and which may besubstituted by 1 or more R₁₁ groups; R₀ is a C1-C6 alkyl that may besubstituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl; R₁₀ is a group R₈,C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro,cyano, C(O)NR₆R₇, phenyl which may be substituted by 1 to 4 R₁₁ groups;R₁₁ is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen,nitro, cyano, or C(O)NR₆R₇; X is carbon or nitrogen; n is 1 or
 2. 2.Compounds, according to claim 1, in which R₂ and R₃ together with N forma 5-14 membered heterocyclic group, which may be substituted by 1 to 3R₁₀ groups.
 3. Compounds, according to claim 1, of general formula (Ia)

in which R, R₁, R₂, R₃ R₄ and X are defined as in claim
 1. 4. Compounds,according to claim 3, of general formula (IIa)

in which R, R₁, R₂, R₄ and R₃ are defined as in claim
 1. 5. Compounds,according to claim 4, in which the group NR₂R₃ represents a 5-6 memberedheterocyclic group, which may be substituted by 1 to 3 R₈ groups. 6.Compounds, according to claim 5, of general formula (IIIa)

wherein R, R₁, R₄ and R₉ are defined as in claim
 1. 7. Compounds,according to claim 1, of general formula (Ib)

in which R, R₁, R₂, R₃ R₄ and X are defined as in claim
 1. 8. Compounds,according to claim 7, of general formula (IIIb)

in which R, R₁, R₂, R₄ and R₃ are defined as in claim
 1. 9. Compounds,according to claim 1 wherein R₁ is C1-C3 alkyl group or halo C1-C3 alkylgroup and R₄ is hydrogen.
 10. Compounds, according claim 1 wherein R isan aryl group selected from: 2,4-dichlorophenyl,2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl,2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl,2-methyl-4-methoxyphenyl, 2-methyl4-chlorophenyl,2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl,2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl,2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl,2-bromo-4-isopropylphenyl, 2-methyl4-cyanophenyl,2-chloro-4-cyanophenyl, 4-methyl-6-dimethylaminopyridin-3-yl,3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and3-chloro-5-tricloromethyl-pyridin-2-yl.
 11. A compound, according claim1 selected in a group consisting from:1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;3-methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile;4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile;6-methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;1-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;1-(4-methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine4-[1,3′]bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.12. A pharmaceutical composition comprising a compound according toclaim 1 in admixture with one or more physiologically acceptablecarriers or excipients.
 13. A method for the treatment of a mammal,including man, in particular in the treatment of conditions mediated byCRF (corticotropin-releasing factor), comprising administration of aneffective amount of a compound according to claim
 1. 14. A method,according to claim 13, in the treatment of depression and anxiety,comprising administration of an effective amount of a compound accordingto claim
 1. 15. A method, according to claim 14, in the treatment of IBS(irritable bowel disease) and IBD (inflammatory bowel disease),comprising administration of an effective amount of a compound accordingto claim 1.